Epidemiological studies in man have demonstrated a correlation of lower incidence of atherosclerotic cardiovascular disease (ACVD) with moderate alcohol intake but the mortality due to ACVD increases with heavy alcohol drinking and alcohol abuse. The consistency of the results among these studies suggests that there may be a threshold in the amount of alcohol consumption (perhaps up to two drinks/day) that the potential benefit effects of alcohol drinking against ACVD cease to exist. Why moderate alcohol consumption protects against ACVD whereas heavy drinking may have the opposite effect remains unclear. Our previous studies have shown that prolonged alcohol drinking increases plasma apo A1 and decreases plasma apo E concentrations in both rodents and humans. We have also found that LDL of human alcoholic patients is chemically modified in vivo resulting in changes in their biological functions and thus exhibits atherogenic characteristics. We hypothesize that alcohol consumption may protect against atherosclerosis, in part, by promoting a favorable plasma lipoprotein profile. On the other hand, chronic consumption of alcohol in large amount is harmful because it may chemically modify LDL in vivo and render LDL more atherogenic and thus overwhelm the anti-atherogenic effects of increasing HDL. To study the effect of alcohol on biological processes in humans is frequently not feasible because of ethical consideration. By contrast, alcohol and dietary intake by small rodents can be rigidly controlled by pair- feeding to exclude nutritional variations which can strongly affect lipid and lipoprotein metabolism. Recently, several lines of transgenic and gene-knockout mice have been developed for the study of atherosclerosis. Some of these transgenic and gene-knockout mice are prone to develop severe atherosclerosis much like in humans. Our preliminary data showed that feeding alcohol to LDL receptor gene- knockout (LDLR -/-) mice and apo E-/- mice impeded the early atherosclerosis induced by an atherogenic diet. Furthermore, it showed that feeding the atherogenic diet sharply decreased serum apo A1 in LDLR-/- mice but alcohol ingestion reversed the decrease of apo A1. Because atherosclerosis is a multifactorial disease, three different transgenic mice, i.e. LDL receptor gene-knockout (LDLR-/-) mice, apo E- /- and human apo B transgenic mice, will be used for the following SPECIFIC AIMS: 1) To test for alcohol effects on atherogenesis using liquid diets containing different concentrations of alcohol. 2) To measure apolipoprotein distributions in plasma lipoproteins to correlate with atherogenesis. 3) To test whether effects of alcohol on serum apolipoproteins A1 and E was at pre- or post-translational levels. 4) To test the effects of alcohol-feeding on the response of macrophages to modified LDLs. 5) To test for alcohol effects on LDL physical properties and biological functions in these three strains of transgenic mice. Combined data obtained from rat and mouse models will provide the basis needed for future study in humans.